tbuckley/cabot-search huggingface dataset:
Induction therapy of toripalimab combined with docetaxel and cisplatin in locally advanced hypopharyngeal squamous cell carcinoma (HPSCC): A single-arm, phase II clinical trial.
Authors: Chunmei Bai, Chenyu Wang, Ning Jia, Xingming Chen, Xiaoli Zhu, Shuai Sun, Xiaohua Shi, Yu Chen, Yaping Luo
Journal: Journal of Clinical Oncology (2023)

6070 Background: PD-1 (programmed cell death protein-1) inhibitors combination with chemotherapy has a significant efficacy and approved indications in the first-line treatment of head and neck squamous cell carcinoma (HNSCC), but the efficacy of these combination therapies in locally advanced hypopharyngeal squamous cell carcinoma (HPSCC) remains unexplored. We conducted a single-arm, phase II trial to assess the efficacy and safety of toripalimab (a novel PD-1 inhibitor) combined with chemotherapy as induction treatment in locally advanced HPSCC. Methods: Patients with locally advanced HPSCC (cT1N+M0 or T2-4NanyM0, AJCC 8.0) were eligible. All patients received 2 cycles of intravenous docetaxel (75mg/m 2 ), cisplatin (75mg/m 2 ) and toripalimab (240mg) on day 1 every 21 days, followed by radical surgery or concurrent chemoradiotherapy (CCRT) with cisplatin (100mg/m 2 , q21d). The primary endpoint was objective response rate (ORR) assessed by investigators per RECIST v1.1. Secondary endpoints were major pathologic response (MPR), 2 year disease-free survival (DFS) rate in patients received surgery, 2 year progression-free survival (PFS) rate in patients received CCRT and 2 year overall survival (OS) rate in all patients. Results: From July 2020 to January 2023, 34 patients (median age: 59, range: 46-72, male: 100%, stag IV: 100%) were enrolled. Patients with stage IVA an IVB disease were 19 (19/34, 55.9%) and 15 (15/34, 44.1%), respectively. 33 patients completed 2 cycles induction treatment and efficacy evaluation (1 patient dropped out). The evaluated ORR was 54.5%, including 3 pts achieving complete response and 15 achieving partial response. PD-L1 status (combined positive score, CPS) were known in 8 patients, ORR were 80% (4/5) and 66.7% (4/6) in patients with CPS≥20 and CPS≥1, respectively, 2 patients with CPS＜1 had stable disease. Treatment-related grade 3-4 adverse events occurred in 45.5% (15/33) of patients, leukopenia (42.4%) and neutropenia (3.1%). Immune-related AEs were acceptable, 1 patient (1/33, 3.0%) experienced grade 2 interstitial pneumonia and 2 patients (2/33, 6.1%) experienced grade 1 rash. In the following treatment, 27 patients (27/33, 81.8%) performed CCRT. 4 patients (4/33, 12.1%) underwent surgery followed by CCRT and 2 patients (2/33, 6.1%) refused further treatment. Among these 17 patients finished CCRT and radiological assessment, 9 patients (9/17, 52.9%) had complete response, 7 patients (7/17, 41.2%) had partial response and 1 patient (1/17, 5.9%) had progressive disease. Survival data are not mature by cut-off date. Conclusions: Induction therapy of toripalimab combined with docetaxel and cisplatin was well tolerated and highly efficient for locally advanced HPSCC. Clinical trial information: NCT04296747 .
Real-world impact of time-to-treatment initiation and initial treatment modality on survival in pancreatic and colorectal cancers.
Authors: Joshua Schwanke, Brooke Patterson, Schelomo Marmor, McKenzie Joy White, Eric Hans Jensen, Christopher Tignanelli, Emil Lou, Ajay Prakash
Journal: Journal of Clinical Oncology (2023)

e15646 Background: Overall survival for patients with pancreatic ductal adenocarcinoma (PDAC) and colorectal cancers (CRC) has increased significantly over the past decade; however, the optimal time-to-treatment initiation (TTI) and initial treatment modality (ITM) have not been defined. These variables have likely been affected by increased adoption and changes in types of neoadjuvant treatment strategies for these cancer types. Thus, we performed a retrospective observational study of TTI and ITM in patients with CRC and PDAC within the MHealth/Fairview medical system. Methods: We identified 424 patients with stage I-III RC and 316 patients with stage I-III PDAC within the MHealth/Fairview system (Minneapolis, MN) from 2011-2021 with North American Association of Central Cancer Registries data enriched by the electronic health record. Patients were stratified by TTI from diagnoses as: 0-7 days, 8-14 days, 15-28 days, 29-42 days, and over 43 days. ITM, defined as initial chemotherapy/chemoradiation, surgery, or radiation, was analyzed independently for patients with rectal cancer (N = 267) and PDAC. Effect of TTI and ITM on overall survival was calculated using a Cox proportional Hazard (CPH) model controlling for clinical stage. Results: TTI was significantly associated with survival in CRC, with patients treated in 8-14 days and 15-28 days showing increased survival over patients treated in over 43 days (HR 0.397, p = 0.007 and HR 0.276 p &lt; 0.001, respectively). There was no significant hazard for TTI and survival in PDAC. We also found that neoadjuvant chemotherapy/chemoradiation had a lower hazard for death in rectal cancer relative to upfront surgery (HR 0.323, p = 0.002), when controlling for stage. Surgery was significantly more likely to be correlated with stage I or II disease than chemotherapy/chemoradiation (68.5% vs 24.7%, p &lt; 0.0001 by Spearman method). There was no significant association between ITM and survival in patients with PDAC. Conclusions: Early treatment for CRC is associated with improved survival in this population, implying that treatment delays decrease the efficacy of curative-intent therapy. Evaluation of treatment modality in the rectal sub-group showed improved outcomes with neoadjuvant chemotherapy and chemoradiation, despite upfront surgery being associated with lower stage. The lack of association between TTI and survival in PDAC is likely related to the relatively poor outcomes observed with this disease and highlights the need for better screening and treatment for resectable disease. These results are notable because they suggest that a thorough workup and appropriate therapy may be more important than rapid treatment.
Establishing functional models of peritoneal carcinomatosis using MicroOrganoSphere (MOS) technology.
Authors: Abdelrahman M.G. Yousef, Aaron McCormick, Amber Smith, Ichiaki Ito, Mahmoud M.G. Yousef, Mohammad A. A. Zeineddine, Beth A Helmink, Michael White, Keith F. Fournier, Daniel Delubac, Xiling Shen, John Paul Y.C. Shen
Journal: Journal of Clinical Oncology (2023)

e16337 Background: Appendiceal adenocarcinomas (AAs) are a rare and heterogeneous mix of tumors for which few preclinical models exist for drug discovery. These tumors are commonly treated with chemotherapy according to best practices developed for colorectal cancer, despite clear evidence that the two cancers are distinctly different in their clinical behavior and molecular profiles. In this study, we created functional tumoroid models (MicroOrganoSpheres or MOS) of peritoneal carcinomatosis from appendix cancer and mesothelioma and used these MOS to test the efficacy of different chemotherapy treatments. Methods: After obtaining informed consent, fresh tumor samples were obtained from 5 patients with peritoneal carcinomatosis undergoing surgical resection at The University of Texas MD Anderson Cancer Center and 5 samples were obtained from previously established PDX models. Tissue was digested using xMRS solution and MOS culture was established. H&amp;E was performed on tissue and paired MOS. Results: Five MOS models were successfully established, including four AA and one primary peritoneal mesothelioma (to our knowledge the first time this has been done from a peritoneal mesothelioma). Four (80%) of the 5 PDX models samples successfully generated MOS. Three out of five from the fresh samples generated p0 MOS, but only one continued to grow (20%). The MOS successfully established from fresh biopsy was a moderately differentiated mucinous adenocarcinoma with GNAS R201C and KRAS G12R mutation, to our knowledge the first time a Patient Derived Organoid (PDO) model of this disease has been created. Identified failure modes were delayed processing times (&gt;48 hours after extraction in 3 out of 5 clinical samples) and low tumor content in samples. Histologically, the MOS recapitulated several important characteristics of the original patients’ tumors, including degree of differentiation, abundance of mucin, and presence of signet ring features. Response of AA MOS models to chemotherapeutic agents and regimes has been evaluated in one model thus far. AAPDX-13, derived from a low-grade mucinous adenocarcinoma, was tested against common CRC treatments: 5-FU (pIC 50 5.90), Oxaliplatin (pIC 50 4.51), SN-38 (pIC 50 5.16). Relative to the mean from multiple CRC MOS, this was less sensitive to 5FU and more sensitive to irinotecan. Conclusions: Novel MOS models for AA and peritoneal mesothelioma were successfully established. MOS recapitulated key histologic features of AA and mesothelioma. Data acquired from this MOS system can aid in identifying appropriate chemotherapy treatments in select patients where there are no existing preclinical disease models.
Circulating tumor DNA to guide furmonertinib monotherapy or combination therapy in advanced EGFR mutant non-small cell lung cancer (NSCLC): A randomized, open-label, multicenter study (FOCUS-C).
Authors: Wenfeng Fang, Jun Jia, Guanming Jiang, Xiaofang Dong, Zongxiao ShangGuan, Zhengxiang Han, Hong Shen, Li Zhang
Journal: Journal of Clinical Oncology (2023)

TPS9150 Background: Detection of EGFR ctDNA after several weeks EGFR-TKIs treatment was an effective method to identify prognosis of advanced EGFR mutant NSCLC patients. Patients with uncleared EGFR ctDNA had shorter progression-free survival (PFS) ( Mack PC et al; CCR 2022). However, whether they can benefit from EGFR-TKI combination therapy has not been reported. Furmonertinib (AST2818), a potent, orally bioavailable, highly brain penetrant, third generation EGFR-TKI with unique chemical structure designed to improve potency and specificity, showed superior efficacy compared with gefitinib as first-line therapy in EGFR mutant NSCLC along with an acceptable safety profile without new signals ( Shi, YK et al.; Lancet Respir Med 2022). We hypothesized that monitoring clearance of EGFR ctDNA in blood could rationally guide subsequent monotherapy or combination therapy with furmonertinib and will improve outcomes in patients with uncleared EGFR ctDNA. Methods: The FOCUS-C study is a multicenter, open-label, randomized study. Patients who are aged 18 years or older and have histologically confirmed, locally advanced or metastatic, stage IIIB, IIIC, or IV unresectable NSCLC with EGFR exon 19 deletions (19Del) or exon 21 Leu858Arg mutation (L858R) on tissue biopsy and plasma will be treated with furmonertinib. Eligible patients with uncleared EGFR 19Del or L858R ctDNA after 3 weeks furmonertinib treatment will be stratified according to EGFR mutation (19Del or L858R), central nervous system metastases (with or without) and detectable accompanying gene aberrances in plasma (with or without) and randomly assigned (2: 2: 1) to receive furmonertinib or furmonertinib plus chemotherapy (pemetrexed and carboplatin for 4 cycles followed by maintenance pemetrexed) or furmonertinib plus chemotherapy plus bevacizumab (pemetrexed, carboplatin and bevacizumab for 4 cycles followed by maintenance pemetrexed and bevacizumab) in 21-day cycles until disease progression, the occurrence of intolerable toxicities, withdrawal of consent, or other discontinuation reasons judged by the investigators. The primary endpoint is PFS between furmoneritnib plus chemotherapy versus furmonertinib alone. Secondary endpoints include PFS, objective response rate, duration of response, disease control rate, overall survival and safety. Several exploratory endpoints will also be evaluated based on ctDNA detection by next-generation sequencing (Genecast, Wuxi, China). The study is enrolling. 34 patients had been enrolled till 2nd Feb 2023. Clinical trial information: NCT05334277 .
Racial disparities in the prevalence of extrathoracic metastases in lung cancer patients and survival: A SEER database study (2010–2019).
Authors: Abdul Rahman Al Armashi, Akram Alkrekshi, Anas Al Zubaidi, Faris Hammad, Dina Elantably, Vien Truong, Tam N.M. Ngo, Debora S. Bruno
Journal: Journal of Clinical Oncology (2023)

e20630 Background: Metastatic disease at the time of lung cancer diagnosis influences therapy choice and prognosis. Metastasis to the brain, bones, and liver may lead to higher morbidity. Differences in the prevalence of metastatic sites among patients (pts) of White (W) and Black (B) race and their association with overall survival need further elucidation. Methods: Utilizing the SEER database from 2010-2019, we identified W and B pts with metastatic small cell (SCLC), squamous cell (SQ-NSCLC), and adenocarcinoma (AD-NSCLC). Only pts with bone, brain, or liver metastasis (mets) at diagnosis were included. Metastatic site prevalence rates were determined. Cox proportional hazard ratios for survival were calculated while controlling for gender, ethnicity, other metastatic sites, chemotherapy, and radiation. Results: Total of 338,411 pts, 11.4% of B race. In SCLC, B pts had a higher prevalence of brain mets, while W pts demonstrated a higher prevalence of bone and liver mets. Survival between W and B pts with SCLC was comparable except for modest superior survival in B pts with liver mets. In SQ-NSCLC, metastatic disease for the 3 sites of interest was more prevalent in B pts, most notably in brain. However, survival did not differ. In AD-NSCLC, B pts were more likely to present with brain and liver mets. B pts with bone mets had inferior survival. Conclusions: Significant differences in patterns of mets at the time of lung cancer diagnosis between W and B pts exist. B pts with SCLC and liver mets had longer survival. Interestingly, B pts with bone mets and SQ-NSCLC had better survival while those with AD-NSCLC fared worse. Multiple factors, including socioeconomic, environmental/smoking patterns and access to healthcare, may have contributed. Further studies are needed. [Table: see text]
A real-world study of TACE combined with regorafenib as a second-line treatment for advanced hepatocellular carcinoma.
Authors: Shaoxing Liu, Song Gao, Jianhai Guo, Fuxin Kou, Xin Zhang, Baojiang Liu, Aiwei Feng, Xiaodong Wang, Hui Chen, Xu Zhu
Journal: Journal of Clinical Oncology (2023)

e16144 Background: Regorafenib is a guideline-recommended second-line systemic drug, and its combination with transarterial chemoembolization (TACE) for the treatment of advanced liver cancer after first-line therapy has been gradually recognized by clinicians. We investigated the efficacy and safety of TACE combined with regorafenib with or without anti-PD-1 immunotherapy as a second line choice for advanced hepatocellular carcinoma (HCC). Methods: In this retrospective study, we retrieved patients with advanced liver cancer who had failed first-line therapy in our center from January 2019 to December 2021, and screened out patients who received TACE combined with regorafenib as second-line therapy. The data of objective response rate (ORR), progression-free survival (PFS) and adverse reactions (ARs) of treatment in these patients were analyzed and summarized. Subgroup analysis of patients with and without PD-1 inhibitors was also performed. Results: A total of 43 eligible patients were screened and treated with TACE in combination with regorafenib in second-line therapy, including 29 patients treated with PD-1 inhibitors. In all patients, one patient had complete response (CR) and 11 patients had partial response (PR), with ORR of 27.91% (12/43) and 24 patients had stable disease (SD), with disease control rate (DCR) of 83.72% (36/43). The median PFS was 10.0 months for all patients in survival follow-up, with PFS rates of 77.65% and 37.17% at 6 and 12 months follow-ups, respectively. Overall survival (OS) rates were 90.49%, 67.03%, and 58.65% at 12, 18, and 24 months, respectively. In subgroup analysis, there was no statistical difference in median PFS between the groups with or without PD-1 inhibitors (11.0 months vs 8.0 months, p=0.229), but there was a trend toward survival benefit in the combined group (hazard ratio/HR 0.62). The incidence of treatment-related ARs in all treated patients was 81.40% (35/43), all grade 1-2. Among ARs, hand-foot syndrome (27.91%), loss of appetite (20.93%), and elevated transaminases (16.28%) were predominant. Conclusions: This study verified the efficacy and safety of TACE combined with regorafenib as second-line therapy for the treatment of advanced HCC after failure of first-line therapy, and the results need to be further justified in future prospective studies with larger sample sizes. [Table: see text]
Effect of MYC-targeting programmable epigenetic mRNA therapeutics on TME and immunotherapy responses.
Authors: Yan Moore, William Senapedis, Kayleigh Gallagher, Elmer Figueroa, Madison Pacaro, Defne Yarar, Eugine Lee, Thomas McCauley
Journal: Journal of Clinical Oncology (2023)

4116 Background: c-MYC is a master transcription factor (TF) critical for multiple cell physiologies. As a pleiotropic TF, MYC regulates the tumor microenvironment (TME) and impacts cancer cell initiation, growth, and survival. Although MYC expression is normally tightly controlled in normal cells, its activity is frequently dysregulated in cancer (e.g., HCC, NSCLC, Burkitt’s lymphoma). A direct MYC targeting anti-cancer agent has remained elusive, largely due the absence of a drug binding pocket and tight autoregulation. The MYC gene and its regulatory elements reside alone within an insulated genomic domain and represents a potential target for gene regulation via an epigenetic approach. Methods: We are developing programmable epigenetic mRNA medicines designed to controllably tune gene expression pre-transcriptionally with high specificity and durability. We have rationally designed MYC-targeted Omega Epigenomic (MYC-OEC: clinical candidate OTX-2002; MYC Lung OEC; mouse surrogate muMYC-OEC) to downregulate MYC expression, thereby selectively killing cancer cells while sparing normal cells. We investigated the role of MYC-OECs in the modulation of the TME and demonstrated in human and mouse tumor models that MYC-OECs enhanced the host immune response. Results: In HCC and NSCLC cell lines (Hep 3B, SKHEP1, H2009 and H460), treatment with MYC-OECs in vitro significantly inhibited PD-L1 surface expression. Using the muMYC-OEC in vivo, we demonstrated tumor growth inhibition (TGI) in Hepa1-6 liver cancer syngeneic tumor models with 70% of the mice exhibiting complete tumor response with good tolerability. Cancer cells used to rechallenge the cured mice failed to grow, demonstrating that muMYC-OEC monotherapy induced immune memory. In addition to inhibiting tumor growth with either muMYC-OEC or checkpoint blockade immunotherapy (CBI; anti-PD-1 or anti-PD-L1) treatment, combination therapy further enhanced TGI. Tumor-infiltrating lymphocyte profiling demonstrated an increase in activated T cells and a reduction in Tregs following combination treatment, resulting in an increased effector T cell to Treg ratio over monotherapy. Depletion of CD4 + , CD8 + and NK cells in vivo prior to single agent or combination treatment demonstrated a requirement for both CD4 + and CD8 + T cell activity for TGI. NK cells were dispensable. Taken together, these data demonstrate that the improved CBI/MYC-OEC combination activity is mediated through the recruitment of activated T cells and reduction of immune suppressive Tregs. Conclusions: These efficacy and tolerability data support the combination of MYC-OEC and CBI treatment in patients with solid tumors. OTX-2002 is currently being evaluated in a Phase 1/2 clinical trial as a monotherapy and in combination with SoC (i.e., TKI and CBIs) for patients with HCC and other solid tumor types known for an association with MYC.
The risk of myocardial infarction and heart failure in colon cancer in the United States: A population-based national study.
Authors: Joanna M. Brell, Dina Elantably, Abdul Rahman Al Armashi, Jiasheng Wang, Faris Hammad, Anas Al Zubaidi, Akram Alkrekshi
Journal: Journal of Clinical Oncology (2023)

e15517 Background: Colon cancer ranks third in cancer mortality and estimated new cases in the United States. Along with the improved treatment and increased participation in screening, there are more than 1.5 million survivors. Venous thromboembolism (VTE) is associated with cancers due to various mechanisms that are common with arterial thromboembolism. Still, there are limited population-based studies on the risk of myocardial infarction (MI) and heart failure (HF) in colon cancer. Methods: Retrospectively we analyzed data from a nationwide commercial database (Explorys, IBM) from 1999 to October 2022. It gathers records from 26 healthcare systems in 50 states with nearly 80 million patients. We identified adults over 18 years old with colon cancer, MI, and HF. In addition, we obtained data on risk factors, including sex, age over 65 years, hypertension (HTN), hyperlipidemia (HLD), diabetes mellitus (DM), atrial fibrillation, obesity, and tobacco use. Multivariable logistic regression (MLR) was used to adjust for the variables collected. All tests were two-sided, and a p-value ≤ 0.05 was considered statistically significant—data presented as odds ratio (OR) with a 95% confidence interval (CI). Results: A population of 69,339,860 was included. Colon cancer was diagnosed in 304,650 (0.4%), MI in 1,691,900 (2.4%), and HF in 2,415,450 (3.5%). Males made 45%. The colon cancer group, compared to the background population, had a higher prevalence of patients aged over 65 years (66.8% vs. 30.7%), HTN (61% vs. 21.1%), HLD (50.7% vs. 16.9%), DM (31.4% vs. 8.8%), obesity (20.7% vs. 8.0%), and tobacco use (12.5% vs. 6.6%). MLR of variable studies (Table). Colon cancer was significantly associated with MI and HF. Conclusions: This is the largest population-based study of the risk of MI and HF in colon cancer in the United States. After adjustment for established risk factors that may confound the result, colon cancer was independently associated with a significant increase in the risk of MI and HF. Raising awareness among oncologists and cardio-oncologists' involvement at the time of diagnosis is essential to optimally and aggressively manage modifiable risk factors. Prospective studies are needed. [Table: see text]